The invention relates to coated pellets, methods for their production and use thereof. Numerous pharmaceutical active ingredients have a bitter taste, e.g. numerous antibiotics, in particular azithromycin, cefixime, cefdinir, cefpodoxime, cefuroxime and clarithromycin. These active ingredients are usually not administered as such, but are administered orally as active ingredient formulations. The active ingredients can be contained, for example, in tablets, capsules, liquids or pellets. The oral intake of medications also generally represents a preferred type of administration for active ingredients with a bitter taste.
It is known that older patients, children and patients with diseases or injuries in the region of the oesophagus occasionally have problems swallowing larger administration forms such as e.g. oblong tablets or capsules. Specific application aids have been developed for these patients to make the intake of oral administration forms easier for them. Thus, special drinking straws are known, in which a pellet formulation containing active ingredient is contained. The patient then takes the pellet formulation by using the drinking straw like a conventional drinking straw for drinking a suitable liquid. The pellets are then transported via the flow of liquid. Reference is made in this context to WO 2003/079957, WO 2004/000202 and WO2004/000264, for example, in their full scope.
However, the formulation of active ingredients with a bitter taste in conventional pellets does not prevent the patient from noticing the bitter taste of the contained active ingredient. Many conventional formulations do not or only inadequately prevent development of the bitter taste of the contained active ingredient. This is associated with the fact that the pellets remain for a brief time in the mouth cavity—and in the transport liquid in the case of intake using a drinking straw—before being swallowed, and this is sufficient for the bitter substance to come into contact with the taste buds on the tongue possibly via saliva. The bitter taste of the active ingredient is then perceived by the patient either during or directly after oral intake. In such cases, the patient occasionally develops a strong aversion to intake of the formulation, which can be detrimental, amongst other things, to the strict adherence to a specific therapeutic schedule. The bitter taste can also trigger a retching reflex that prevents effective oral administration or at least makes this difficult. This problem occurs in particular in children and older patients.
There are different approaches for masking the bitter taste of active ingredients in the prior art. For example, the addition of conventional sweeteners or flavourings for masking the unpleasant taste is generally known. These sweeteners or flavourings give the formulation its own taste that should conceal the bitter taste of the active ingredient. It is possible in many cases to mask the taste of moderately bitter pharmaceutical active ingredients by such a type of taste masking. However, this type of taste masking is inadequate in the case of extremely bitter active ingredients.
Moreover, it is known in the prior art to provide pellets with coverings to mask the bitter taste of the contained active ingredient. The materials from which these film coverings are made usually comprise polymers, which are insoluble or poorly soluble in water and are not, or at least not completely, dissolved by saliva, so that the core containing the active ingredient is protected by the film covering and the bitter taste of the contained active ingredient is thus masked for the duration of the intake. However, such film coverings have the disadvantage that they also have a considerable influence on the release behaviour. Thus, as a result of the insolubility or poor solubility of the film covering in aqueous media the film covering does not dissolve or dissolves only slowly in the stomach, so that a delay or even retardation of the release of the active ingredient frequently results. This delay or retardation can be entirely advantageous and desirable, depending on what type of active ingredient is concerned and what medical indication the formulation is provided for. Thus, polymers insoluble in acid medium can be used, for example, as coating materials that are resistant to stomach acid in order to allow the active ingredient to only be released in the intestinal environment. Examples of stomach acid-resistant coating materials are Eudragit® L-55, Eudragit® L, Eudragit® S or Eudragit® FS or cellulose derivatives such as e.g. HP55, HPMCAS or CAP.
The retardation action of the film covering and the physiological location of release can be controlled by mixing water-soluble substances as pore formers with the insoluble polymer. If such a film covering is exposed to an aqueous medium, then the pore formers dissolve out of the film covering and leave behind water-filled pores, through which the active ingredient can escape. The release of the active ingredient can be regulated via the size and number of pores. Usually, the dissolution of the water-soluble pore formers takes o long that the retention time in the mouth—and in the transport liquid in the case of intake using a drinking straw—is not sufficient to even release active ingredient from the formulation. An effective masking of the bitter taste of the active ingredient can thus be achieved in this way. An example of such a film covering is Eudragit® L-55 with saccharose or citric acid as water-soluble pore formers. Such film coverings are often unsuitable for administration forms that should release the active ingredient quickly without retardation (rapid release or immediate release), since the formation of the pores takes a certain period of time because the water-soluble pore former has to dissolve out. Acceleration of the release of active ingredient can occur, if necessary, by increasing the amount of water-soluble pore former. Thus, experiments with pellets provided with a covering of Eudragit® L-55 and an adequate amount of citric acid demonstrate that the bitter taste of the active ingredient can be effectively masked, while a release of the active ingredient can also be achieved under in vitro conditions that is comparable with that of pellets that are not covered (immediate release).
However, a disadvantage of these conventional film coverings is that in vivo the bioavailability of the active ingredient in administration forms provided with these film coverings under fed status test conditions does not correspond to the bioavailability of conventional administration forms, in particular those with very quick release (rapid release, immediate release, e.g. liquid formulations or disintegrated pellets without covering), i.e. there is no bioequivalence.
Fed status test conditions are always necessary in the case of bioequivalence studies, for example, where bioequivalence is to be demonstrated for medicinal substances or drugs, which according to the accompanying instructions should be taken with food or with the intake of food demonstrate a bioavailability that has changed compared to fasted status. This is also stipulated in the official approval guidelines. In this context, reference can be made, for example, to Guidance for Industry, U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and Research (CDER): Bioavailability and Bioequivalence Studies for Orally Administered Drug Products and Food-Effect Bioavailability and Fed Bioequivalence Studies; and GUIDANCE FOR INDUSTRY, Bioequivalence Requirements: Comparative Bioavailability Studies Conducted in the Fed State, Health Canada, file number: 05-114865-164, Jun. 8, 2005 in their full scope.
It is known that the administration of an active ingredient with food (fed status) compared to administration of the active ingredient without food (fasted status) can cause a decrease, delay or increase in active ingredient absorption, but can also have no effect at all on the active ingredient absorption (cf. e.g. N. Yasui-Furukori et al., J Clin Pharmacal, 55, 2003, 382-8). Conditions in the gastrointestinal tract differ fundamentally as a result of food intake, in particular with respect to motility, pH value, ion concentration, buffering capacity, osmolarity, liquid volume and concentration of surface-active substances (bile acid concentration).
The effect of food on the pharmacokinetics on cefpodoxime proxetil when administered orally as a suspension is explained, for example, by G. S. Hughes et al., Clin Pharmacol Ther 1989, 46, 674-85; G. L. Kearns et al., Pediatr Infect Dis J., 1998, 17(9), 799-804; and M. T. Borin et al., Antimicrob Agents Chemother, 1995, 273-5. The effect of food on the pharmacokinetics of cefuroxime axetil when administered orally or administered intravenously is explained, for example, by A Finn et al., Biopharm Drug Dispos. 1987, 8(6), 519-26. Azithromycin is also preferably administered in practice under fed status conditions (cf. e.g. G. W. Amsden et al., J Antimicrob Chemother 2001, 47, 61-6).